IFI35 Promotes Renal Cancer Progression by Inhibiting pSTAT1/pSTAT6-Dependent Autophagy

SIMPLE SUMMARY: Interferon-induced protein 35 (IFI35) plays an important role in virus-related immune inflammatory responses. However, the biological significance and function of IFI35 in cancer is still not well understood. Our goal is to explore whether IFI35 could be used as tumor marker or a therapeutic target for renal cell cancer (RCC). Our results showed that IFI35 expression was significantly increased in 200 RCC specimens, and its expression was negatively associated with poor overall or disease-specific 5-year patients’ survival. Next, we explored the mechanism and function of IFI35 in RCC. The results demonstrated that knockdown of IFI35 could inhibit the proliferation and invasion of renal cancer cells by enhancing the STAT1/STAT6 phosphorylation (pSTAT1/pSTAT6)-dependent autophagy. Likewise, the knockdown of IFI35 also suppressed the tumor growth or lung metastasis of renal cancer by enhancing the induction of autophagy. This study aims to provide a theoretical basis for IFI35 as a potential diagnosis and therapeutic target for RCC or other cancers with high levels of IFI35. ABSTRACT: Interferon-induced protein 35 (IFI35), is currently acknowledged to govern the virus-related immune inflammatory responses. However, the biological significance and function of IFI35 in renal cell cancer (RCC) is still not well understood. Here, IFI35 expression and function were investigated in RCC tissues, renal cancer cells, and animal models. The results showed that IFI35 expression was significantly increased in 200 specimens of RCC patients. We found that higher IFI35 levels were significantly correlated with poor RCC prognosis. In human cell lines, the knockdown of IFI35 suppressed the malignant behavior of renal cancer cells. Similarly, the IFI35 knockdown resulted in significant inhibition of tumor progression in the subcutaneous or lung metastasis mouse model. Furthermore, the knockdown of IFI35 promoted the induction of autophagy by enhancing the autophagy-related gene expression (LC3-II, Beclin-1, and ATG-5). Additionally, blockade of STAT1/STAT6 phosphorylation (pSTAT1/pSTAT6) abrogated the induced autophagy by IFI35 knockdown in renal cancer cells. The autophagy inhibitor 3-MA also abolished the prevention of tumor growth by deleting IFI35 in renal cancer models. The above results suggest that the knockdown of IFI35 suppressed tumor progression of renal cancer by pSTAT1/pSTAT6-dependent autophagy. Our research revealed that IFI35 may serve as a potential diagnosis and therapeutic target for RCC.